Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties

Chwalenia, Katarzyna; Oieni, Jacopo; Zemła, Joanna; Lekka, M.; Ahlskog, Nina; Coenen-Stass, Anna M.L.; McClorey, Graham; Wood, Matthew J.; Lomonosova, Yulia; Roberts, Thomas C.

doi:10.1016/j.omtn.2022.08.033

Cited by 4 publications

(5 citation statements)

References 66 publications

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“…Given the close association between EIM alterations and changes in muscle composition, the PPMO dosing regimen used in this study may normalize skeletal muscle abnormalities in mdx mice. In addition, a previous report that dystrophin increased by exon skipping improved muscle stiffness in mdx mice [24] could support our results in the EIM study. Further studies regarding the dose-dependency and intervention period of PPMO are required to investigate the amount and time course of dystrophin protein that would be adequate to recover from muscle composition abnormalities in mdx mice.…”

Section: Discussionsupporting

confidence: 91%

“…A peptide Pip9b2 (Ac-RXRRBRRFQILYRBRXRB-OH, where 'X' was aminohexanoic acid, and 'B' was βalanine)-conjugated PMO (PPMO) [24] that was designed to induce skipping of Dmd exon 23 in mice, was manufactured at Takeda Pharmaceutical Company Limited. PPMO was dissolved in saline at a concentration of 2 mg/mL and then warmed for 10 min at 65 ˚C followed by vortex mixing.…”

Section: Treatment With a Peptide-conjugated Pmomentioning

confidence: 99%

“…Regarding potential treatment for DMD, there is growing evidence that the antisense oligonucleotides (ASOs)-mediated exon skipping approach can restore functional dystrophin proteins and improve muscle function, by promoting splicing out of dystrophin mutations [19][20][21]. Preclinical studies have shown that in vivo exon skipping using cell-penetrating peptide-conjugated antisense phosphorodiamidate morpholino oligomers (PMOs) is a powerful strategy [22][23][24][25]. Among them, Pip9b2-conjugated PMO (PPMO) exhibited dose-dependent exon skipping and dystrophin protein restoration in the skeletal muscles of mdx mice [24].…”

Section: Introductionmentioning

confidence: 99%

“…Preclinical studies have shown that in vivo exon skipping using cell-penetrating peptide-conjugated antisense phosphorodiamidate morpholino oligomers (PMOs) is a powerful strategy [22][23][24][25]. Among them, Pip9b2-conjugated PMO (PPMO) exhibited dose-dependent exon skipping and dystrophin protein restoration in the skeletal muscles of mdx mice [24]. A potential challenge in turning these treatment approaches into clinical practice is verifying the change in functional dystrophin expression in patients with DMD, which is now achieved only by burdensome muscle biopsy [1].…”

Section: Introductionmentioning

confidence: 99%

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Electrical impedance myography detects dystrophin-related muscle changes in mdx mice

Hiyoshi,

Zhao,

Baba

et al. 2023

Preprint

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Background The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) causes chronic skeletal muscle inflammation and degeneration. Therefore, the restoration of functional dystrophin levels is a fundamental approach for DMD therapy. Electrical impedance myography (EIM) is an emerging tool that provides noninvasive monitoring of muscle conditions and has been suggested as a treatment response biomarker in diverse indications. Although magnetic resonance imaging (MRI) of skeletal muscles has become a standard measurement in clinical trials for DMD, EIM offers distinct advantages, such as portability, user-friendliness, and reduced cost, allowing for remote monitoring of disease progression or response to therapy. To investigate the potential of EIM as a biomarker for DMD, we compared longitudinal EIM data with MRI/histopathological data from an X-linked muscular dystrophy (mdx) mouse model of DMD. In addition, we investigated whether EIM could detect dystrophin-related changes in muscles using antisense-mediated exon skipping in mdx mice. Methods Longitudinal MRI/ magnetic resonance spectroscopy (MRS) data of muscle T2 and fat, and three EIM parameters with histopathology were obtained from the hindlimb muscles of wild-type (WT) and mdx mice. In the EIM study, a cell-penetrating peptide (Pip9b2) conjugated antisense phosphorodiamidate morpholino oligomer (PPMO), designed to induce exon-skipping and restore functional dystrophin production, was administered intravenously to mdx mice. Results MRI imaging in mdx mice showed higher T2 intensity at 6 weeks of age in hindlimb muscles compared to WT mice, which decreased at ≥ 9 weeks of age. In contrast, EIM reactance began to decline at 12 weeks of age, with peak reduction at 18 weeks of age in mdx mice. This decline was associated with myofiber atrophy and connective tissue infiltration in the skeletal muscles. Repeated dosing of PPMO (10 mg/kg, 4 times every 2 weeks) in mdx mice led to an increase in muscular dystrophin protein and reversed the decrease in EIM reactance. Conclusions These findings suggest that muscle T2 MRI is sensitive to the early inflammatory response associated with dystrophin deficiency, whereas EIM provides a valuable biomarker for the noninvasive monitoring of subsequent changes in skeletal muscle composition. Furthermore, EIM reactance has the potential to monitor dystrophin-deficient muscle abnormalities and their recovery in response to antisense-mediated exon skipping.

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Section: Discussionsupporting

confidence: 91%

Section: Treatment With a Peptide-conjugated Pmomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Electrical impedance myography detects dystrophin-related muscle changes in mdx mice

Hiyoshi,

Zhao,

Baba

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In contrast, we have observed that antisense oligonucleotide-mediated exon skipping with peptide-phosphorodiamidate morpholino oligonucleotide (PMO) conjugates results in within-fiber uniform dystrophin distribution that is independent of dose (see related manuscript). 73 …”

Section: Discussionmentioning

confidence: 99%